Genetic Variant EOMES:p.Pro533Thr (chr3-27717591-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001278182.2(EOMES):c.1597C>A(p.Pro533Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P533S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

EOMES
NM_001278182.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.98

Publications

0 publications found

Variant links:

Genes affected

EOMES (HGNC:3372): (eomesodermin) This gene belongs to the TBR1 (T-box brain protein 1) sub-family of T-box genes that share the common DNA-binding T-box domain. The encoded protein is a transcription factor which is crucial for embryonic development of mesoderm and the central nervous system in vertebrates. The protein may also be necessary for the differentiation of effector CD8+ T cells which are involved in defense against viral infections. A similar gene disrupted in mice is shown to be essential during trophoblast development and gastrulation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

EOMES Gene-Disease associations (from GenCC):

microcephaly-polymicrogyria-corpus callosum agenesis syndrome
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet

EOMES links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22139081).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EOMES	NM_001278182.2 link	c.1597C>A	p.Pro533Thr	missense_variant	Exon 6 of 6	ENST00000449599.4	NP_001265111.1	O95936-4B7Z4K0
EOMES	NM_005442.4 link	c.1540C>A	p.Pro514Thr	missense_variant	Exon 6 of 6		NP_005433.2	O95936-1B7Z4K0
EOMES	NM_001278183.2 link	c.712C>A	p.Pro238Thr	missense_variant	Exon 6 of 6		NP_001265112.1	O95936-3
EOMES	XM_005265510.5 link	c.1478C>A	p.Pro493His	missense_variant	Exon 7 of 7		XP_005265567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EOMES	ENST00000449599.4 link	c.1597C>A	p.Pro533Thr	missense_variant	Exon 6 of 6	1	NM_001278182.2	ENSP00000388620.1	O95936-4
EOMES	ENST00000295743.8 link	c.1540C>A	p.Pro514Thr	missense_variant	Exon 6 of 6	1		ENSP00000295743.4	O95936-1
EOMES	ENST00000461503.2 link	c.712C>A	p.Pro238Thr	missense_variant	Exon 6 of 6	2		ENSP00000487112.1	O95936-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

D;.;.

Eigen

Benign

0.069

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Uncertain

0.043

PhyloP100

3.0

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.5

N;D;.

REVEL

Uncertain

0.36

Sift

Benign

0.045

D;D;.

Sift4G

Benign

0.083

T;D;D

Polyphen

0.057

B;.;.

Vest4

0.26

MutPred

0.32

Loss of catalytic residue at P514 (P = 0.0036);.;.;

MVP

0.73

MPC

0.68

ClinPred

0.96

GERP RS

4.5

Varity_R

0.20

gMVP

0.43

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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3-27717591-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over